Intestinal drug absorption
Bio-conjugation combined with efflux in the enterocyte determines intestinal drug absorption
The sesquiterpene lactone nobilin exhibits high membrane permeability, low relative absorption and fast bioconversion forming glucuronide, cysteine conjugate, and glutathione conjugate in the Caco-2 cell culture model. These metabolites are transported by P-gp (the first two), apical MRP2 and basal MRP3 and possibly MRP1 out of the cell. Inhibition of efflux resulted in diminished bioconjugation (kinetic constant kdc) and improved absorption, Fa.
This is an interesting interplay between phase II metabolism and carrier mediated membrane transport that can be exploited to increase intestinal drug absorption.
In this study efflux inhibitors were employed in the Caco-2 model and data evaluation was performed by kinetic multi-compartment modeling.